The Role of Bicaudal-C in Polycystic Kidney Disease
Bicaudal-C 在多囊肾病中的作用
基本信息
- 批准号:8529504
- 负责人:
- 金额:$ 32.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-08-21 至 2015-07-31
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated RegionsAddressAdultAmphibiaAnteriorAutosomal Dominant Polycystic KidneyAutosomal Recessive Polycystic KidneyBasic ScienceBindingBinding SitesBiochemical PathwayBiogenesisBiologicalBiological ModelsCaenorhabditis elegansCell divisionCellsChildChronic Kidney FailureCompanionsCystCystic kidneyDataDefectDevelopmentDialysis procedureDiseaseDisease ProgressionDisease modelDrosophila genusDrug FormulationsElementsEmbryoEnd stage renal failureEpithelialFutureGenesHealthHereditary DiseaseHomologous GeneHumanInheritedKidneyKidney TransplantationLengthLiquid substanceMessenger RNAMetanephric structureMicroRNAsModelingMolecularMusMutant Strains MiceMutateMutationNephronsOrganismPKD2 proteinPathogenesisPatternPhenotypePolycystic Kidney DiseasesPronephric structureProteinsRNA BindingRattusRegulationRegulator GenesRoleSiteSystemTestingTherapeutic InterventionXenopusZebrafishanimal model developmentbasecitrate carrierclinical applicationdisease phenotypegenetic analysishomologous recombinationinsightloss of functionmalformationmouse modelnephrogenesisnovelpolycystic kidney disease 1 proteinpreventprotein expression
项目摘要
DESCRIPTION (provided by applicant): Polycystic Kidney Diseases (PKD) are the leading cause of end-stage renal failure and are characterized by the development of renal cysts along the entire length of the nephron. They require extensive treatments, such as dialysis and kidney transplantation. Only limited forms of therapy for PKD exist, since the molecular mechanisms underlying the formation of renal cysts are still poorly understood. Over the years, considerable progress has been made in identifying genes mutated in human forms of PKD and in the development of animal models to study the pathogenesis of these detrimental diseases. Besides mouse and rat PKD models, the more primitive pronephric kidney of Xenopus or zebrafish has emerged as an alternative model system to study the molecular mechanisms underlying the epithelial malformations causing PKD. With its fast development and ease of molecular manipulations, the pronephric kidney is an ideal companion system to the study of PKD in humans or mice. In this proposal we will use the mouse metanephros and the amphibian pronephros to study the RNA binding molecule Bicaudal-C. Mice lacking Bicaudal-C protein develop renal cysts as early as embryonic day 15.5. Cyst formation is first detected in the glomerulus, but can later be detected along the entire length of the nephron. Similarly, in Xenopus, loss-of-Bicaudal-C induces a "PKD-like" phenotype in the pronephros. Importantly, the molecular mechanism of Bicaudal-C activity in kidney development and its connection to the genes mutated in human PKD, i.e. Polycystin-1, Polycystin-2 and Polyductin/Fibrocystin is still not understood. This proposal will address these questions. We will test the hypothesis that Bicaudal-C is a translational regulator of genes involved in Polycystic Kidney Disease. It is based on four observations: (1) Bicaudal-C mutant mice have reduced Polycystin-2 mRNA and protein levels before the onset of cyst formation. (2) The regulation of Polycystin-2 is posttranscriptional. (3) Bicaudal-C protein is localized to P-Bodies and has been shown in Drosophila and C. elegans to regulate a selected group of mRNAs at the posttranscriptional level. (4) Many PKD genes have evolutionary conserved miRNA binding sites in their 3' UTR. If successful, this study will provide novel insights to the underlying biological and biochemical pathways leading to the renal cyst formation in PKD. It will integrate one of the least understood PKD genes into the existing paradigms of PKD. As such, it will be directly applicable to future studies of PKD and may provide a new angle for therapeutic interventions.
描述(由申请人提供):多囊性肾脏疾病(PKD)是终末期肾衰竭的主要原因,其特征是沿整个肾脏长度沿着肾脏囊肿的发展。他们需要广泛的治疗方法,例如透析和肾脏移植。仅存在有限的PKD治疗形式,因为肾脏囊肿形成的分子机制仍然知之甚少。多年来,在识别以人类形式的PKD形式和动物模型的发展以研究这些有害疾病的发病机理的基因方面取得了长足的进步。除了小鼠和大鼠PKD模型外,异爪蟾或斑马鱼的更原始的隆起肾脏已成为研究引起PKD上皮畸形的分子机制的替代模型系统。俯卧肾脏的快速发展和易于分子操作,是研究人类或小鼠PKD的理想伴侣系统。在此提案中,我们将使用小鼠替诺夫罗斯和两栖动物pronephros研究RNA结合分子bicauaudal-c。在胚胎第15.5天,缺乏双龙C蛋白的小鼠早于肾囊肿。首先在肾小球中检测到囊肿的形成,但稍后可以沿着肾单位的整个长度检测到。同样,在爪蟾中,杀伤性损失诱导了脑力plonephros中的“ PKD样”表型。重要的是,肾脏发育中双毛-C活性的分子机制及其与人类PKD突变的基因的联系,即多囊蛋白-1,polycystin-2和polycystin-2和polyductin/fibrocystin尚不清楚。该建议将解决这些问题。我们将检验以下假设:Bicauaudal-C是参与多囊肾脏疾病的基因的转化调节因子。它基于四个观察结果:(1)Bicauaudal-C突变小鼠在囊肿形成发作之前降低了多囊蛋白-2 mRNA和蛋白质水平。 (2)Polycystin-2的调节是转录后的。 (3)Bicauaudal-C蛋白局部定位于P体型,并已在果蝇和秀丽隐杆线虫中显示,以调节转录后水平的一组MRNA。 (4)许多PKD基因在其3'UTR中具有进化保守的miRNA结合位点。如果成功,这项研究将为基本的生物学和生化途径提供新的见解,从而导致PKD肾脏囊肿的形成。它将将最知识的PKD基因之一整合到PKD的现有范例中。因此,它将直接适用于PKD的未来研究,并可能为治疗干预提供一个新的角度。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Oliver Wessely其他文献
Oliver Wessely的其他文献
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{{ truncateString('Oliver Wessely', 18)}}的其他基金
The Role of Bicaudal-C in Polycystic Kidney Disease
Bicaudal-C 在多囊肾病中的作用
- 批准号:
7918955 - 财政年份:2009
- 资助金额:
$ 32.3万 - 项目类别:
The Role of Bicaudal-C in Polycystic Kidney Disease
Bicaudal-C 在多囊肾病中的作用
- 批准号:
8585587 - 财政年份:2009
- 资助金额:
$ 32.3万 - 项目类别:
The Role of Bicaudal-C in Polycystic Kidney Disease
Bicaudal-C 在多囊肾病中的作用
- 批准号:
8332924 - 财政年份:2009
- 资助金额:
$ 32.3万 - 项目类别:
The Role of Bicaudal-C in Polycystic Kidney Disease
Bicaudal-C 在多囊肾病中的作用
- 批准号:
8335453 - 财政年份:2009
- 资助金额:
$ 32.3万 - 项目类别:
The Role of Bicaudal-C in Polycystic Kidney Disease
Bicaudal-C 在多囊肾病中的作用
- 批准号:
7727579 - 财政年份:2009
- 资助金额:
$ 32.3万 - 项目类别:
Xenopus Bicaudal-C a Model for Polycystic Kidney Disease
非洲爪蟾双尾-C 多囊肾病模型
- 批准号:
7287296 - 财政年份:2005
- 资助金额:
$ 32.3万 - 项目类别:
Xenopus Bicaudal-C a Model for Polycystic Kidney Disease
非洲爪蟾双尾-C 多囊肾病模型
- 批准号:
6901574 - 财政年份:2005
- 资助金额:
$ 32.3万 - 项目类别:
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